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Persona 2: Innocent Sin begins three years after the events of the first Persona. The location is Sumaru City, a large fictional metropolitan area set in modern day Japan. Sumaru City becomes cursed after events during the beginning of the game that cause any rumor that spreads enough to become true. Yukino Mayuzumi returns from the first game, already familiar with demons and capable of using her Persona.

The silent protagonist of the game is Tatsuya Suou. Tatsuya is dragged into the plot by Lisa Silverman, a fellow student whom idolizes Tatsuya, when a conflict between Seven Sisters High School (Sevens) and Kasugayama High School (Cuss High) begin. The two come across Eikichi Mishina, the self-entitled boss of Cuss High. After getting into a fight, the three play a game summoning the Joker, a mysterious antagonist rumored to appear before anyone that calls him. Anyone who fails to tell Joker their wishes, either because they lack one or refuse to tell, has their "ideal energy" stolen, reducing them to ambition-less shells called Shadow Selves. Joker claims that the three students had done something terrible to him in the past, and is angered when they do not recognize him. Swearing revenge and wielding an odd Crystal Skull, he departs, leaving the trio confused and eager to investigate the Joker. Later on they make a point of saying that Tatsuya and the Joker look alike.

Eventually, the three students are joined by Maya Amano and her friend, Yukino. The five then search for Joker, the source of all rumors that spread becoming reality. Their search leads the group to clash with a cult-like following known as the Masked Circle. It is later revealed that the original Masked Circle was the group of friends including Tatsuya, Maya, Lisa, Eikichi, and Jun when they were all kids. After debunking numerous rumors and defeating several members of the Masked Circle, the group meets with Joker, who then reveals himself to be Jun Kurosu, the fifth childhood friend and member of the original Masked Circle. Eventually, the widely spread rumor that the Fuhrer had survived World War II with his secret forces, the Last Battalion, surfaces and his forces invade Sumaru City. Tatsuya and the others fight off both remaining Masked Circle members and the Last Battalion soldiers to obtain the crystal skulls, defeating their own Shadows in the process.

Towards the end of Innocent Sin, Tatsuya and the others board an alien spaceship known as the Xibalba, another rumor that had spawned into reality. In the deepest parts of Xibalba, the group finds the Fuhrer, wielding the Spear of Destiny (the spear that pierced Jesus Christ that is said to leave a mortal wound the second it strikes flesh) and defeats him.

At the conclusion of the game, it is revealed that all of the events had been orchestrated by Nyarlathotep in an attempt to show that the negatives of humanity would outshine the positives, contrary to Philemon's beliefs. Nyarlathotep then takes his true form and fights Tatsuya and the others. After the fight, Nyralathotep strikes Maya with the Spear of Destiny, killing her quickly. With the prophecy fulfilled, the Earth's rotation suddenly stops, destroying everything on the surface of the planet, save for Sumaru City. Philemon tells Tatsuya that there is a way to prevent Maya's death and stop Nyralathotep from destroying the world. Tatsuya agrees to create a new timeline in which Nyarlathotep is not successful, in exchange for everyone's memories.

The remake has an extended port with an updated user interface, new character portraits designed by Shigenori Soejima and heavily improved controls, but keeps most of the game's original gameplay systems. The battle system, however, is overhauled and based on the one used by the game's sequel, Persona 2: Eternal Punishment, but adds adjustable difficulties and battle cut-in portraits like in Persona 3 and Persona 4. The remake also includes the whole new Sumaru Climax Theatre, which features sidestories written by various other authors from Atlus. The stories are like quests and in the end, players will have to face a boss. Additionally, players can make their own quests in the Japanese version of the game (the feature was omitted from the English release).

In addition, players can select whether they want to hear the old soundtrack of the original game or listen to about 100 new arrangements of the original soundtrack by Shoji Meguro, the game's director and composer. The arrangements make use of guitar sounds, J-Pop, and other modern music genres. The voices have been remastered for the Japanese version, but Atlus did not re-record anything due to some of the original voice actors having retired.

There is an all-new opening movie created by Satelight, with music by Lotus Juice. Lovers of the game's first incarnation will notice that the original opening is included, too.

The PS1 version of Persona 2: Innocent Sin was never initially released in North America or Europe for unknown reasons. It is assumed that it was never released overseas because of the possibility of Tatsuya Suou having a homosexual relationship with fellow party member Jun Kurosu, and the appearance of Adolf Hitler.

In an interview with GameInformer, Gail Salamanca, a member of Atlus USA's localization team, mentions another possible reason for a lack of localization was simply due to the developers not having the resources, manpower, or being able to schedule the time to localize the game for an American audience, with the team already having been underway with development of Eternal Punishment, and adds that "...We pretty much had to let it go. Though It wasn't for the lack of b--ching and moaning by the US staff", likely referring to the aforementioned issues.

Despite this, the game received a fan translation patch for use with PS1 emulators, which gives the game English text, but leaves the Japanese voices intact. Atlus knows about the fan patch and hasn't, so far, made any attempts to remove the patch from the internet.

Persona 2: Innocent Sin was referenced in Persona 3. The game's subtitle serves as the title for a popular MMORPG in the world of the English version of Persona 3, and is known as "Innocent Sin Online". During the course of the game, the protagonist has the opportunity to play the game on Sundays and on holidays and is required to establish the Hermit Social Link. In Persona 3 Portable the MMORPG "Innocent Sin Online" and consequently the Social Link from it can only be initiated if the male protagonist was chosen. In addition, the protagonist's character in "Innocent Sin Online" is called Tatsuya and the person who represents the Hermit Social Link (who the protagonist interacts with in the MMORPG) is named Maya.

In both Innocent Sin and Eternal Punishment, the game's developers make frequent cameos.

The PSP remake of Innocent Sin is the first Megami Tensei game to get its European release announced before the North American release.